Abstract
We evaluated changes in patent ductus arteriosus (PDA) diagnosis and treatment from 2012 through 2021 in a network of U.S. academic hospitals. PDA treatment decreased among infants born at 26-28 weeks but not among infants born at 22-25 weeks. Rates of indomethacin use and PDA ligation decreased while acetaminophen use and transcatheter PDA closure increased.
Keywords: Patent Ductus Arteriosus, Preterm Infant, Secular Trends
Patent ductus arteriosus (PDA) is a common problem among extremely preterm infants1 and is associated with mortality and neonatal morbidity2 but a causal relationship has not been established. 2,3 Secular changes in approach to PDA diagnosis and management over the past decade have been reported. First, there has been a trend towards a more conservative approach to intervention in some centers. 4,5 Second, there are reports of a decrease in the diagnosis and treatment, both medical and surgical, of the PDA.6-8
Several recent clinical trials have reported no difference in outcomes or, in some instances, potential harm in patients who received routine PDA treatment compared with conservative management.9-14 In contrast, several observational studies have reported potential harm among extremely preterm infants whose PDAs were managed conservatively.5,15 The US Food and Drug Administration recently approved the Amplatzer Piccolo Occluder, a device for transcatheter closure of the PDA in infants as small as 700 grams. Recent evidence suggests that transcatheter PDA closure is a safe and effective alternative to surgical PDA closure.16,17
Early targeted PDA treatment is another strategy that has become popular with the increased use of neonatologist-performed echocardiography.18 It is unclear whether these new developments have changed how PDA is evaluated and managed in NICUs. There are no recent data on PDA management trends specific to tertiary care academic centers in the United States. The objective of this study is to describe temporal changes in PDA diagnosis and treatment in a network of large academic NICUs in the Unites States.
Methods
Design
We performed a retrospective cohort study of preterm infants born at 22 0/7 through 28 6/7 weeks’ gestation at centers participating in the National Institute of Child Health and Human Development Neonatal Research Network (NRN) between 1/1/2012 and 12/31/2021. Only hospitals that were part of the NRN during the entire study period were included. Infants who died before 12 postnatal hours, were born outside of NRN hospitals, had major congenital anomalies, or were enrolled in the NRN PDA trial, were excluded.
Data Collection
We used prospectively collected data from the NRN Generic Database. Participating centers received local institutional review board approval for data collection. Per individual hospital guidelines, data were collected under a waiver of consent or after informed consent was obtained from parents or legal guardians. Information on PDA diagnosis and treatment was prospectively entered by trained data abstractors. PDA diagnosis (“yes or no”) was defined as documentation of clinical or echocardiographic evidence of left-to-right PDA physiology determined by the clinical team in routine care. Medical PDA treatment was defined as any medication used specifically to induce PDA closure (e.g., indomethacin, ibuprofen, acetaminophen) regardless of timing, duration, or dose. Prophylactic indomethacin for intraventricular hemorrhage prevention was defined as administration of indomethacin within the first 24 hours after birth and was not considered as medical PDA treatment. Procedural PDA closure included catheter and transthoracic surgical closure. Data on the use of acetaminophen and transcatheter PDA closure were not collected prior to 2016. Descriptive baseline neonatal demographics (e.g., gestational age, birthweight, sex) were also collected.
Statistical Analyses
Annual PDA diagnosis and treatment rates were analyzed using the Cochran-Armitage trend test to evaluate time-related changes in proportion for the entire cohort and for two gestational age strata: 22 0/7 through 25 6/7 weeks and 26 0/7 through 28 6/7 weeks. These two gestational age strata were chosen based on published differences in the rate of spontaneous PDA closure between these groups.19 Trends of pharmacological treatment and procedural PDA closure were also evaluated. Multivariable logistic regression comparing PDA treatment (yes/no) over years was performed for both gestational age strata with adjustments for center, small for gestational age (SGA), antenatal steroid exposure, gestational age (in weeks), early-onset sepsis, infant sex, and mechanical ventilation on day 7. These variables were prespecified based on clinical relevance. Statistical significance was defined as a two-sided p-value <0.05 with no adjustment for multiple testing. All analyses were done using SAS (v.9.4).
Results
Among 23 continuously participating hospitals from 2012- 2021, there were 12,982 eligible infants. The mean (+/− standard deviation) gestational age and birth weight were 26.3 weeks (+/−1.7 weeks) and 855 g (+/−247g), respectively. Approximately 60% of infants were born at gestational ages 26-28 weeks. Overall, 44% of infants had a diagnosis of PDA and 25% of infants received medical or procedural PDA treatment. Demographics and baseline characteristics of infants are presented in Supplementary Table 1.
Entire Cohort
For the entire cohort, there was an increase in PDA diagnosis from 43.8% to 45.8% from 2012 to 2021 (p = 0.03). There was also a decrease in medical treatment or procedural closure from 28.0% to 24.3% (p = 0.03, Figure 1a, Table 1). While use of indomethacin decreased from 21.6% in 2012 to 8.6% in 2021 (p<0.0001), use of acetaminophen increased from 1.6% in 2016 to 12.9% in 2021 (p<0.0001, Figure 1b, Table 1). Ibuprofen use was unchanged. Although surgical PDA ligation decreased from 8.4% to 2.1% (p<0.0001), transcatheter PDA closure increased from 0.8% in 2016 to 4.8% in 2021 (p<0.0001, Figure 1b, Table 1).
Figure 1.
PDA diagnosis and treatment from 2012-2021 for the entire study cohort
Table 1.
PDA diagnosis and treatment from 2012-2021 for the entire study cohort
| Study Year | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Characteristic | 2012 (N=1432) |
2013 (N=1387) |
2014 (N=1348) |
2015 (N=1339) |
2016 (N=1308) |
2017 (N=1288) |
2018 (N=1306) |
2019 (N=1287) |
2020 (N=1189) |
2021 (N=1098) |
Trend test p-value 1 |
| PDA diagnosis, n (%) | 626 (43.8%) | 589 (42.5%) | 561 (41.6%) | 568 (42.5%) | 559 (42.9%) | 567 (44.1%) | 585 (44.9%) | 562 (43.7%) | 535 (45.0%) | 502 (45.8%) | 0.03 |
| Medical treatment, n (%) | 374 (26.2%) | 323 (23.3%) | 311 (23.1%) | 302 (22.6%) | 276 (21.2%) | 312 (24.3%) | 290 (22.3%) | 283 (22.0%) | 271 (22.8%) | 255 (23.2%) | 0.08 |
| Procedural closure, n (%) | 120 (8.4%) | 86 (6.2%) | 94 (7.0%) | 104 (7.8%) | 93 (7.1%) | 85 (6.6%) | 85 (6.5%) | 86 (6.7%) | 91 (7.7%) | 72 (6.6%) | 0.32 |
| Medical treatment or Procedural closure, n (%) | 400 (28.0%) | 344 (24.8%) | 339 (25.1%) | 323 (24.2%) | 311 (23.8%) | 328 (25.5%) | 313 (24.0%) | 300 (23.3%) | 289 (24.3%) | 267 (24.3%) | 0.03 |
| Indomethacin, n (%) | 309 (21.6%) | 217 (15.6%) | 223 (16.5%) | 203 (15.2%) | 170 (13.0%) | 176 (13.7%) | 164 (12.6%) | 122 (9.5%) | 127 (10.7%) | 94 (8.6%) | <.0001 |
| Ibuprofen, n (%) | 76 (5.3%) | 129 (9.3%) | 108 (8.0%) | 116 (8.7%) | 115 (8.8%) | 136 (10.6%) | 119 (9.1%) | 125 (9.7%) | 86 (7.2%) | 73 (6.7%) | 0.29 |
| Acetaminophen 2, n (%) | 21 (1.6%) | 32 (2.5%) | 54 (4.1%) | 92 (7.2%) | 112 (9.4%) | 141 (12.9%) | <.0001 | ||||
| Surgery, n (%) | 120 (8.4%) | 86 (6.2%) | 94 (7.0%) | 104 (7.8%) | 83 (6.4%) | 61 (4.8%) | 50 (3.8%) | 45 (3.5%) | 39 (3.3%) | 22 (2.0%) | <.0001 |
| Catheterization 2, n (%) | 10 (0.8%) | 24 (1.9%) | 36 (2.8%) | 43 (3.3%) | 52 (4.4%) | 53 (4.8%) | <.0001 | ||||
P-value comes from the Cochran-Armitage trend test.
Acetaminophen and catheterization were not collected until 2016
Gestational Age Subgroup Analyses
For the subgroup of infants born at 22-25 weeks’ gestational age, PDA diagnosis increased over time from 57.1% to 61.6% (p =0.004). Approximately 37% underwent any medical PDA treatment or procedural closure and there was no change over time. Medical treatment of PDA (approximately 34%) and procedural closure (approximately 12%) remained constant during the study period (Figure 2a, Supplementary table 2).
Figure 2.
PDA diagnosis and treatment from 2012-2021 for gestational age subgroups
Among infants born at 26-28 weeks’ gestational age, PDA diagnosis occurred in approximately 35% and did not change over the study period (Figure 2b). There was a decrease in medical treatment or procedural closure (19.6% to 15.1%, p=0.0007). Medical treatment decreased over time from 18.8% to 14.5% (p=0.0005), while procedural closure (approximately 4%) remained constant throughout the study period (Figure 2b, Supplementary table 2).
Adjusted Analyses
Multivariable regression analysis showed that birth year had no association with PDA medical treatment or procedural closure (expressed as per year) among infants born at 22-25 weeks after adjustment for potential confounding factors aOR: 0.99 [ 95% CI: 0.97, 1.01], p=0.35, Table 2)._The decrease in medical treatment or procedural closure across years among the infants born at 26-28 weeks remained statistically significant after adjustment for other risk factors (aOR: 0.96 [ 95% CI: 0.94, 0.98], p=0.0004, Table 2).
Table 2.
Multivariate logistic regression for PDA medical treatment and procedural closure by gestational age subgroups
| Characteristic | Adjusted Odds Ratio (95% Confidence Interval) |
p-value |
|---|---|---|
| 220/7 – 256/7 Weeks | ||
| Birth year 1 | 0.99 (0.97-1.01) | 0.35 |
| Small for gestational age | 1.32 (1.01-1.72) | 0.04 |
| Antenatal steroid | 0.98 (0.76-1.26) | 0.86 |
| Early onset sepsis | 1.44 (0.98-2.1) | 0.06 |
| Male | 1.06 (0.93-1.2) | 0.41 |
| Gestational age (weeks) 1 | 0.85 (0.79-0.92) | <0.0001 |
| Mechanical ventilation on day 7 | 1.91 (1.61-2.27) | <0.0001 |
| 260/7 – 286/7 Weeks | ||
| Birth year 1 | 0.96 (0.94-0.98) | 0.0004 |
| Small for gestational age | 0.96 (0.76-1.18) | 0.67 |
| Antenatal steroid | 1.41 (1.1-1.81) | 0.006 |
| Early onset sepsis | 1.47 (0.84-2.58) | 0.18 |
| Male | 1.20 (1.06-1.37) | 0.005 |
| Gestational age (weeks) 1 | 0.62 (0.57-0.67) | <0.0001 |
| Mechanical ventilation on day 7 | 3.46 (3.00-3.99) | <0.0001 |
Odds ratio from one unit increase in continuous variable.
Discussion
The optimal approach to diagnosis and management of PDA in preterm infants has been a focus of substantial research for decades but remains controversial. Our study from a large network of academic centers in the United States demonstrated that, although PDA medical treatment or procedural closure decreased among infants born at 26 to 28 weeks, there was no corresponding change among infants born at 22 to 25 weeks. Additionally, we showed an increase in the diagnosis of PDA in extremely preterm infants, driven exclusively in infants born 22 to 25 weeks’ gestation.
Our data reveal a differential approach to PDA management in infants generally categorized as extremely preterm. Our findings are consistent with a natural history study of PDAs conducted in two European NICUs, showing the PDA may behave differently in infants born at the earliest gestational ages; ongoing ductal patency for > 60 days was noted in 50% of patients born at < 26 weeks’ gestation.19 Although multiple randomized clinical trials have not demonstrated benefit of routine or early targeted PDA treatment,9-14 these trials have faced significant criticisms including for lacking representation of the most premature infants and imprecise methods of patient selection related to hemodynamic significance in enrolled patients.20,21 Therefore, some experts have questioned whether current evidence can confidently be applied to extremely preterm infants born <26 weeks’ gestation. To further complicate matters, several recent observational studies have suggested potentially harmful effects of conservative PDA management in the youngest of the extremely preterm infants.5,15 Recent hypothesis-generating evidence suggests that a targeted approach to early PDA management, based on a standardized and comprehensive adjudication of hemodynamic significance of PDA, may reduce mortality and morbidity in this population.22,23 These data suggest that clinical trials exclusively of infants born at <26 weeks with a clear definition of hemodynamic significance and a standardized approach to intervention are needed to guide clinical management.
Our data show increasing adoption of conservative PDA management in preterm infants born at 26-28 weeks of gestation, as shown in other studies.6-8,24,25 The observed pattern of decreased indomethacin use and increased acetaminophen use, along with increased ibuprofen use in infants born at <26 weeks’ gestation (data not shown), is supported by evidence regarding the balance of safety and efficacy of acetaminophen and ibuprofen compared with indomethacin. 26 However, data on safety and efficacy of acetaminophen for PDA treatment in extremely preterm infants <28 weeks are limited and additional research is needed. 27
Our study also showed a shift in how clinicians approach procedural PDA closure. While there was no change in overall procedural closure rates for both the entire cohort and two subgroups, consistent with previous reports, surgical ligation rates have declined. 6-8 Transcatheter PDA closure rates have increased since 2016 such that, by 2021, there were more than twice as many episodes of transcatheter PDA closure as surgical ligation. This trend has evolved despite calls for caution by experts in the field due to lack of evidence.28,29 A randomized clinical trial (PIVOTOL trial, NCT05547165) to evaluate the efficacy of transcatheter PDA closure compared with conservative management is currently underway in 23 study sites in the United States.
Our study has several important limitations. First, although data were prospectively collected by trained research staff using standardized processes and quality checks, there was no standardized echocardiography protocol or agreed definition of a hemodynamically significant PDA, which is a likely contributor to practice variance between and within sites. Secondly, details of hemodynamic measures, duration of PDA exposure, and timing of diagnosis or treatment were not captured. Third, it is not possible to verify that administration of indomethacin within the first 24 hours after birth was exclusively as a prophylactic intervention and not as early targeted PDA treatment. Fourth, data on the acetaminophen use and transcatheter PDA closure were not collected until 2016. Fifth, no data are available on reasons for changes in PDA diagnosis or management, whether they resulted from policies, practice drift, or underlying clinical changes.
In conclusion, in a large cohort of extremely preterm infants born at academic centers in the United States, diagnosis of PDA increased from 2012 to 2021 with secular changes in treatment patterns. Although PDA treatment decreased among infants born at 26-28 weeks, treatment patterns were unchanged among infants born at 22-25 weeks. Treatment with acetaminophen and transcatheter PDA closure became more common during this period. The impact of these secular changes on mortality and neonatal morbidity require further investigation.
Supplementary Material
Footnotes
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Conflicts of Interest statement: Dr. Kaluarachchi serves as a consultant for ONY Biotech Inc. Dr. Backes has following disclosures; Abbott Laboratories: funding of ongoing multicenter trial, in partnership with National Institutes of Health, entitled PIVOTAL (NCT05547165). Abbott Laboratories has no part in the design or execution of PIVOTAL. Dr. McNamara serves as a consultant for Abbot Laboratories and Aspect Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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